ABSTRACT: Modulation Therapeutics is developing a first in class cyclic peptide coined MTI-101 for the treatment of multiple myeloma. The company currently has a license for the parent molecule which has been awarded a patent covering the intellectual property for both composition of matter and use in cancer in the US and Europe. Modulation Therapeutics is now poised to further advance this class of compounds by the development of a second generation derivative which is PEGylated. MTI-101 is unique with respect to chemical space and mechanism of action. Treatment of myeloma cells with MTI-101 stimulates a CD44 complex resulting in activation of the necroptotic pathway and a robust and sustained increase in intracellular calcium levels leading to cell death. Importantly, MTI-101 is i) more active in patient specimens derived from patients relapsing on therapy compared to specimens obtained from newly diagnosed patients and ii) demonstrates robust synergy when combined with the proteasome inhibitor bortezomib. The goal of the Phase I grant will be to determine the in vivo efficacy and circulating half-life of the PEGylated analog compared to the parent molecule MTI-101. We predict that PEGylation of the molecule will increase the circulating efficacious dose and increase the terminal half-life leading to increased therapeutic index of the molecule. The PEGylated analog will be tested using a syngeneic myeloma in vivo model system. The goals of the Phase II application will be to perform non-GLP and GLP toxicity in rodent (rat) and non-rodent (dog) species, design the Phase I clinical trial and completion of the IND package to the FDA. Additionally, Modulation Therapeutics will invest early into the discovery of companion diagnostics to guide precision therapy for the anticipated Phase III clinical trial. Discovery of companion diagnostics will be accomplished by ex-vivo testing of primary myeloma (CD138 positive) cells using an organotypic model system coupled to gene expression profiling. Preliminary data has identified determinants of calcium flux (Ero1L) expression and necroptosis (BIRC3, TNFAIP3) as putative predictive biomarkers of response. We anticipate early discovery work focused on primary specimens will allow for further validation in phase I-11 clinical trials leading to a potential precision medicine guided phase III clinical trial.